Atherosclerosis and Lipoproteins

Gamma Glutamyl Transferase and Metabolic Syndrome,

Cardiovascular Disease, and Mortality Risk
The Framingham Heart Study
Douglas S. Lee, Jane C. Evans, Sander J. Robins, Peter W. Wilson, Irene Albano, Caroline S. Fox,
Thomas J. Wang, Emelia J. Benjamin, Ralph B. D’Agostino, Ramachandran S. Vasan

Objective—To determine whether serum ␥-glutamyl transferase (GGT) predicts cardiovascular disease (CVD) morbidity
and mortality, accounting for temporal changes in known CVD risk factors and C-reactive protein (CRP).
Methods and Results—In 3451 Framingham Study participants (mean age 44 years, 52% women) we examined the
relations of GGT with CVD risk factors, and prospectively determined the risk of new-onset metabolic syndrome,
incident CVD, and death. GGT was positively associated with body mass index, blood pressure, LDL cholesterol,
triglycerides, and blood glucose in cross-sectional analysis (P⬍0.005). On follow-up (mean 19 years), 968 participants
developed metabolic syndrome, 535 developed incident CVD, and 362 died. The risk of metabolic syndrome increased
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with higher GGT (multivariable-adjusted hazard ratio [HR] per SD increment log-GGT, 1.26 [95%CI; 1.18 to 1.35]).
Adjusting for established CVD risk factors (as time-dependent covariates updated quadriennially) and baseline CRP, a
1-SD increase in log-GGT conferred a 13% increase in CVD risk (P⫽0.007) and 26% increased risk of death
(P⬍0.001). Individuals in the highest GGT quartile experienced a 67% increase in CVD incidence (multivariable-
adjusted HR 1.67, 95%CI; 1.25 to 2.22).
Conclusion—An increase in serum GGT predicts onset of metabolic syndrome, incident CVD, and death suggesting that
GGT is a marker of metabolic and cardiovascular risk. (Arterioscler Thromb Vasc Biol. 2007;27:127-133.)
Key Words: biomarkers 䡲 gamma glutamyl transferase 䡲 risk factor 䡲 cardiovascular disease
䡲 metabolic syndrome 䡲 mortality

G amma;-glutamyl transferase (GGT) has been regarded

as a biomarker of hepatobiliary disease and alcohol
consumption/abuse.1 However, GGT is elaborated by extra-
hepatic tissues including the kidney, epididymis, fibroblasts,
lymphocytes, and lung.2– 4 Accumulating experimental evi-
dence suggests an important role for GGT in extracellular
catabolism of glutathione, the principal thiol antioxidant in
humans. GGT enhances the availability of cysteine to pro-
mote intracellular glutathione (GSH) resynthesis, thereby
counteracting oxidant stress.2,5,6 GGT adsorbs onto circulat-
ing low-density lipoprotein cholesterol (LDL) and can cata-
lyze its oxidation.7 It is expressed in the atheromatous core of
coronary plaques, where it colocalizes with oxidized LDL
and foam cells.8 GGT may also be proinflammatory, because
it mediates interconversion of the glutathione-containing
inflammatory mediator leukotriene C4 into leukotriene D4.9
See page 4
Parallel evidence from epidemiological studies suggest that
higher serum GGT is associated with development of cardio-
vascular disease (CVD) risk factors, including diabetes,
hypertension, dyslipidemia,10 –13 and the metabolic syn-
drome.10 GGT levels correlate positively with novel cardio-
vascular risk factors such as C-reactive protein (CRP), fibrin-
ogen, F2-isoprostanes,14 and inversely with antioxidant
levels.15 Prior studies associated increased GGT with mortal-
ity attributable to ischemic heart and cerebrovascular dis-
ease,16 –18 but have not addressed whether serum GGT reflects
greater burden of CVD risk factors12,13,19 or whether GGT has
incremental prognostic utility beyond these risk factors.20,21
Although prior studies have had unique strengths, they did
not adjust for established cardiovascular risk factors or
CRP16,22–24 and had limited end point selection.24

Original received August 3, 2006; final version accepted October 25, 2006.
From the Institute for Clinical Evaluative Sciences and University Health Network (D.S.L.), University of Toronto, Canada; the National Heart, Lung,
and Blood Institute’s Framingham Heart Study (J.C.E., S.J.R., C.S.F., T.J.W., E.J.B., R.B.D., R.S.V.), Framingham, Mass; the Endocrine-Metabolic
Laboratory (I.A.), Department of Medical and Surgical Sciences, University of Padova, Italy; the Department of Medicine (P.W.W.), Medical University
of South Carolina, Charleston; the Mathematics Department (R.B.D.), Boston University, Boston, Mass; the Cardiology Division (T.J.W.), Massachusetts
General Hospital, Harvard Medical School, Boston, Mass; the Cardiology Section (E.J.B., R.S.V.) and the Department of Preventive Medicine and
Epidemiology (R.S.V.), Boston University School of Medicine, Boston, Mass.
Correspondence to Douglas S. Lee, MD, PhD, Institute for Clinical Evaluative Sciences, Division of Cardiology, University Health Network,
University of Toronto, Rm G-106, 2075 Bayview Ave, Toronto, Ontario, M4N 3M5 Canada. E-mail dlee@ices.on.ca
© 2006 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at http://www.atvbaha.org DOI: 10.1161/01.ATV.0000251993.20372.40

127
 128 Arterioscler Thromb Vasc Biol. January 2007
We examined the cross-sectional clinical correlates of
serum GGT and evaluated, longitudinally, whether higher
levels predicted future CVD events and mortality in the
Framingham Heart Study. We hypothesized that increasing
serum GGT would be associated with elevated risk of
new-onset metabolic syndrome, incident CVD, and all-cause
mortality after accounting for established and novel cardio-
vascular risk factors. We postulated that GGT would predict
CVD risk even after adjusting for vascular risk factors as
time-dependent variables during follow-up.
Methods
Study Participants
The Framingham Offspring Study began in 1971 with the enrollment
of 5124 offspring of the original cohort participants (and their
spouses).25 The second examination cycle (1978 –1982), was at-
tended by 3853 offspring participants (1864 men, 1989 women). Of
these, 402 were excluded for the following reasons: missing GGT
data (n⫽234, 6%), prevalent CVD (n⫽151, 4%), and missing
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covariate data (n⫽17, 0.4%). Prior CVD was defined as presence of
coronary heart disease (myocardial infarction, coronary insuffi-
ciency, angina pectoris), peripheral vascular disease (intermittent
claudication), cerebrovascular disease (stroke or transient ischemic
attack), or heart failure.26 At each quadrennial Heart Study exami-
nation, participants underwent standardized measurements of blood
pressure (BP), anthropometry, medical history, physical examina-
tion, and laboratory assessment of cardiovascular risk factors. All
participants provided written informed consent and the study proto-
col was approved by the Institutional Review Board of the Boston
Medical Center.
Measurements and Definitions
Systolic and diastolic BP were the average of two physician-obtained
measurements performed after participants had rested at least 5 minutes
in a sitting position, using a mercury sphygmomanometer. Hypertension
was defined as a systolic BP ⱖ140 mm Hg or a diastolic BP
ⱖ90 mm Hg, or the use of antihypertensive medication. Current
smoking was self-reported and was defined as having smoked cigarettes
regularly within the prior year. Alcohol consumption was defined based
on self-reported average weekly intake. Serum triglycerides, total and
HDL cholesterol, and blood glucose were measured after an overnight
fast. Diabetes was defined by fasting blood glucose ⱖ126 mg/dL or the
use of oral hypoglycemic agents or insulin.
Participants underwent phlebotomy after an overnight fast (be-
tween 10 to 12 hours), typically between 7.30 AM and 9 AM. Blood
was immediately centrifuged, and plasma and serum specimens were
stored at ⫺20°C until assayed. Uniform measurement of GGT
activity in serum was performed using spectrophotometry by detect-
ing the liberation of p-nitroaniline at 405 nm, resulting from the
reaction of ␥-glutamyl-p-nitroanilide ⫹ glycylglycine (Quest Diag-
nostics [MedPath]).27 High-sensitivity C-reactive protein (CRP) was
measured with a Dade Behring BN100 nephelometer from speci-
mens also obtained at the second offspring examination cycle. The
average intra-assay coefficient of variation for CRP was 3.8%.
Cross-Sectional Correlates of GGT
We evaluated the association of baseline serum GGT with CVD risk
factors and clinical covariates including age, sex, systolic and
diastolic BP, hypertension, LDL and HDL cholesterol, serum tri-
glycerides, fasting blood glucose, diabetes, body mass index (BMI),
smoking status, and alcohol consumption. We compared serum GGT
levels according to presence of metabolic syndrome at baseline,
using modified National Cholesterol Education Program (NCEP)
criteria, which required at least three of: (1) elevated triglycerides,
ⱖ150 mg/dL; (2) HDL cholesterol ⬍40 mg/dL [men] or ⬍50 mg/dL
[women]; (3) BP ⱖ130 mm Hg systolic, ⱖ85 mm Hg diastolic, or on
antihypertensive therapy; (4) fasting blood glucose ⱖ100 mg/dL;
and (5) BMI ⱖ30 kg/m2.28 We substituted BMI for increased waist
circumference because measurements of waist were not obtained at
baseline examination.
Prospective Follow-Up for Incident Events
Participants were followed prospectively for development of meta-
bolic syndrome, incident CVD (fatal or non-fatal coronary heart
disease, peripheral vascular disease, cerebrovascular disease, or heart
failure), and death over a maximum follow-up duration of 20 years.
All CVD events and deaths were systematically reviewed by a
three-investigator panel after evaluating all available office and
hospitalization records, laboratory test results, death certificates, and
autopsy reports.
Statistical Analysis
Cross-Sectional Correlates of GGT
The distribution of GGT values was right-skewed, therefore a natural
log-transformation was applied. To account for an upward shift in
log-GGT in men relative to women, we standardized the distribution
(mean⫽0, SD⫽1) within each sex. The distributions of serum
triglyceride and alcohol consumption were skewed, and were also
log-transformed. Cross-sectional correlates of GGT were identified
using sex-pooled multiple linear regression analysis. Each potential
correlate was examined separately in age/sex-adjusted models. Vari-
ables that were statistically significant at ␣⫽0.05 in these models
were evaluated in multivariable analysis with forward stepwise
selection; covariates significant at ␣⫽0.15 were retained.
Longitudinal Analysis of GGT and Clinical Events
We used Cox proportional hazards regression to examine the
association of baseline GGT with: (1) metabolic syndrome, (2)
incident CVD, and (3) all-cause mortality, over 20 year follow-up.
We constructed Cox models for pooled sexes because formal tests of
interaction (sex⫻log-GGT) were not statistically significant for any
outcome. Initially, we determined the risk associated with a one-
standard deviation increment in standardized log-transformed GGT.
Cutpoints for sex-specific quartiles were defined based on the GGT
distribution of all participants at baseline (prior to exclusions). We
compared the risk of events in quartiles 2 to 4 relative to the lowest
quartile, and also tested for linear trend across quartiles.
For new-onset metabolic syndrome, the primary analysis exam-
ined events over the entire study duration (20 years), after excluding
participants with metabolic syndrome at baseline. We also examined
the risk of metabolic syndrome according to GGT during short-term
follow-up (8-years). New-onset metabolic syndrome was defined by
presence of the modified NCEP diagnostic criteria at any subsequent
quadriennial examination.29 Because ascertainment of metabolic
syndrome required attendance at Heart Study examinations (wheras
CVD or death are ascertained irrespective of Heart Study visits), we
terminated follow-up at the last examination date if ⬎2 consecutive
examination cycles were unattended. Cox models were adjusted
initially for factors unrelated to the metabolic syndrome definition:
age, sex, alcohol consumption, and log-CRP. In secondary analysis,
we evaluated whether GGT predicted new-onset metabolic syndrome
after additional adjustment for BMI, fasting blood glucose, systolic
and diastolic BP, serum triglycerides, and smoking.
For analyses relating GGT to risk of incident CVD and death, we
constructed age/sex-adjusted cumulative incidence curves to illus-
trate risk across GGT quartiles. Cox models estimating risk of
incident CVD and mortality were adjusted for age, sex, BMI,
diabetes, systolic BP, antihypertensive treatment, total/HDL choles-
terol ratio, current smoking, and alcohol consumption at baseline.
Additionally, we adjusted for serum creatinine concentration and
education level (postsecondary versus non) as an indicator of
socioeconomic status in CVD models. Furthermore, we adjusted for
aspartate and alanine aminotransferases (AST, ALT), because re-
ports have linked these enzymes to CVD and metabolic syn-
drome.30,31 Additionally, we adjusted for: (1) baseline CRP; (2)
baseline CRP and all other covariates modeled as time-dependent
variables (updated at each subsequent quadrennial Framingham
 Lee et al Gamma Glutamyl Transferase and CVD Risk and Mortality 129

TABLE 1. Baseline Participant Characteristics by Sex-Specific GGT Quartile

Q1 Men Q2 Men Q3 Men Q4 Men
1–11 12–16 17–24 25–99
Total Women Women Women Women
Sex-Specific Serum GGT Level (units/liter) Sample 1– 6 7–9 10 –13 14 – 88
Age, years (SD)† 44 (10) 42 (10) 42 (10) 45 (10) 46 (9)
Women, n (%) 1790 (52) 356 (44) 546 (57) 421 (53) 467 (53)
Body mass index (kg/m2)†
Mean, SD 25.6 (4.3) 24.6 (3.5) 25.0 (4.0) 25.7 (4.4) 27.0 (5.0)
⬍25, n (%) 1721 (50) 484 (60) 520 (54) 381 (48) 336 (38)
25–29, n (%) 1250 (36) 257 (32) 339 (35) 313 (39) 341 (38)
ⱖ30, n (%) 480 (14) 63 (8) 100 (11) 107 (13) 210 (24)
Alcohol consumption, n (%)*†
None 811 (24) 213 (27) 235 (24) 197 (25) 166 (19)
ⱕ14/wk (M), ⱕ7/wk (F) 1738 (50) 476 (59) 506 (53) 405 (50) 351 (39)
⬎14/wk (M), ⬎7/wk (F) 902 (26) 115 (14) 218 (23) 199 (25) 370 (42)
Systolic BP, mm Hg (SD)† 122 (16) 118 (14) 119 (15) 123 (17) 127 (17)
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†
Diastolic BP, mm Hg (SD) 78 (10) 75 (8) 76 (10) 79 (10) 81 (9)
Hypertension, n (%)† 602 (17) 78 (10) 124 (13) 165 (21) 235 (26)
Treated hypertension, n (%)† 327 (9) 31 (4) 60 (6) 71 (9) 165 (19)
Lipid levels (SD)
Total cholesterol, mg/dL† 203 (38) 191 (36) 198 (36) 207 (39) 216 (38)
HDL cholesterol, mg/dL 49 (13) 49 (13) 49 (13) 48 (14) 48 (14)
Total/HDL ratio† 4.5 (1.6) 4.2 (1.3) 4.3 (1.4) 4.7 (1.7) 4.9 (1.7)
LDL cholesterol, mg/dL† 130 (35) 122 (33) 127 (34) 134 (37) 137 (35)
†
Triglycerides (serum), mg/dL* 105 (80) 81 (51) 91 (60) 108 (73) 139 (109)
Aspartate aminotransferase (AST), IU/L (SD) 21.1 (11.7) 18.1 (7.8) 19.1 (9.6) 20.8 (11.2) 26.3 (15.0)
Alanine aminotransferase (ALT), IU/L (SD) 25.6 (17.7) 19.4 (8.7) 21.7 (13.3) 25.5 (13.4) 35.7 (25.3)
Serum creatinine concentration, mg/dL (SD) 1.16 (0.24) 1.15 (0.23) 1.15 (0.23) 1.18 (0.24) 1.16 (0.24)
Fasting blood glucose, mg/dL (SD)† 98 (19) 96 (16) 96 (14) 99 (17) 103 (25)
Diabetes, n (%)† 121 (4) 18 (2) 20 (2) 30 (4) 53 (6)
Current smoker, n (%)† 1254 (36) 252 (31) 349 (36) 287 (36) 366 (41)
CRP, mg/L, median (IQR)*† 1.02 (2.06) 0.65 (1.24) 0.82 (1.67) 1.11 (2.21) 1.79 (3.02)
IQR⫽Interquartile Range; * tests for trend across quartiles performed using log-transformed values; P for quartile trend ⬍0.001
†

examination attended). We examined the discrimination of models
that included clinical covariates and log-GGT with and without
log-CRP to determine the incremental value of the latter after
accounting for GGT, using the c-statistic. In Cox models, we
confirmed that the assumption of proportionality of hazards was
met.32 Statistical analyses were performed using SAS version 8.2
(Cary, NC) and a two-sided probability value ⱕ0.05 was considered
statistically significant.
Results
Cross-Sectional Correlates of GGT
Participants in higher GGT quartiles were older, had higher
BMI, and were more likely to have hypertension, and elevated
lipids, fasting blood glucose, and CRP (Table 1; P⬍0.001 for
quartile trend). In the highest quartile, 81.4% of men and 86.9%
of women had GGT values within the normal reference range
(eg, men ⱕ50 U/L, women ⱕ40 U/L). Cross-sectionally, pres-
ence of the metabolic syndrome was associated with higher
GGT in men (24.9⫾15.3 versus 18.9⫾14.7 U/L; P⬍0.001) and
women (19.8⫾15.0 versus 11.4⫾9.2 U/L; P⬍0.001). In stepwise
multiple regression models (see the supplemental materials, avail-
able online at http://atvb.ahajournals.org), log-GGT was positively
associated with age (P⫽0.009), male sex, smoking, BMI, LDL
cholesterol, serum triglycerides, alcohol consumption, diastolic BP,
hypertension treatment (Pⱕ0.001 for all), and fasting blood glucose
(P⫽0.004). The above factors explained 33% of the interindividual
variability in GGT; sex, serum triglycerides, and alcohol consump-
tion were principal correlates explaining a large degree of variation.
There was weak positive correlation of log-GGT with log-CRP
(Pearson’s r⫽0.27, P⬍0.001), which was of consistent magnitude
in men (r⫽0.26) and women (r⫽0.27).
Serum GGT and Incidence of the
Metabolic Syndrome
On follow-up, 419 participants (16%, 192 women) developed
metabolic syndrome at 8 years, and 968 individuals (37%,
479 women) developed metabolic syndrome over a 20-year
period. In multivariable Cox models adjusted for age, sex,
alcohol consumption, and CRP, higher GGT was associated
with greater risk of developing the metabolic syndrome with
a 134% (8-year) to 76% (20-year) increased risk in the top
 130 Arterioscler Thromb Vasc Biol. January 2007

TABLE 2. Hazards Ratios for Metabolic Syndrome Onset According to GGT Levels
Log-GGT, 1-SD Quartile Quartile Quartile Quartile Quartile
Increment 1 2 3 4 Trend
Onset of Metabolic Syndrome within 8 years
Age/sex-adjusted 1.39* Referent 1.40† 1.76* 2.26* 1.30*
(1.26–1.52) (1.04–1.87) (1.30–2.39) (1.69–3.01) (1.19–1.42)
Adjusted for age, sex, and alcohol 1.45* Referent 1.46† 1.83* 2.54* 1.35*
(1.32–1.60) (1.08–1.96) (1.35–2.48) (1.89–3.41) (1.23–1.48)
Additional adjustment for CRP 1.38* Referent 1.51‡ 1.64‡ 2.34* 1.30*
(1.25–1.53) (1.11–2.06) (1.19–2.27) (1.72–3.19) (1.18–1.43)
Onset of Metabolic Syndrome within 20 years
Age/sex-adjusted 1.29* Referent 1.21† 1.49* 1.85* 1.23*
(1.21–1.38) (1.01–1.44) (1.23–1.80) (1.54–2.22) (1.16–1.30)
Adjusted for age, sex, and alcohol 1.33* Referent 1.23† 1.53* 1.99* 1.26*
(1.24–1.42) (1.03–1.48) (1.26–1.85) (1.65–2.40) (1.19–1.33)
Additional adjustment for CRP 1.26* Referent 1.23† 1.36‡ 1.76* 1.20*
(1.18–1.35) (1.02–1.49) (1.11–1.66) (1.45–2.13) (1.12–1.27)
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Value of 1-SD log-GGT⫽0.6

†
P⬍0.05, ‡Pⱕ0.01, *Pⱕ0.001

quartile relative to the lowest (Table 2). In models evaluating In multivariable analyses of mortality, the risk increased
log-GGT, a 1-SD increment in log-CRP was associated with across GGT quartiles, remaining robust even after adjustment
a 1.38-fold (95%CI; 1.25 to 1.53, P⬍0.001) and 1.26-fold for log-CRP, and risk factors modeled as time-varying covari-
(95%CI; 1.18 to 1.35, P⬍0.001) risk of metabolic syndrome ates (Table 4). Accounting for log-CRP and all other risk factors
at 8 and 20 years, respectively. The association of GGT with as time-varying covariates, a 1-SD increment in log-GGT was
new-onset metabolic syndrome remained robust in models associated with a 26% increased risk of death. A 1-SD increment
adjusted for serum AST and ALT (data not shown). in log-CRP was associated with a 1.31-fold (95%CI; 1.16 to
Adjusting for age, sex, BMI, fasting glucose, systolic BP, 1.47, P⬍0.001) risk in the latter models. The associations of
diastolic BP, log-triglycerides, alcohol consumption, smoking GGT with incident CVD and death were maintained after
status, and log-CRP, the association of GGT with metabolic adjustment for serum AST and ALT (data not shown).
syndrome remained significant. The hazards ratios (HR) per
Adjusting for clinical covariates (eg, age, sex, BMI, dia-
increment in GGT quartile were 1.14 (95%CI; 1.04 to 1.26,
betes, systolic BP, total/HDL cholesterol ratio, current smok-
P⬍0.01) and 1.09 (95%CI; 1.02 to 1.16, P⬍0.01) in Cox
ing, alcohol consumption) and log-GGT, the c-statistic for
models with 8-year and 20-year follow-up, respectively.
CVD risk was 0.785 (95%CI; 0.766 to 0.804). When log-CRP
Serum GGT and CVD and Mortality Risk was added, the c-statistic increased minimally to 0.786
A total of 65 900 person-years of observation was available in 3451 (95%CI; 0.767 to 0.805). Similarly, the model for mortality
participants for incident CVD and death. On follow-up (mean
19.1⫾3.0 years), 535 participants (15.5%; 173 women) experienced
incident CVD, and 362 individuals died (10.5%; 131 women).
Age/sex-adjusted cumulative incidence of CVD and death (Figures
1 and 2) displayed an increasing gradient of risk across GGT
quartiles (log-rank P⬍0.001 for both outcomes).
In multivariable models adjusting for established risk
factors and CRP, log-GGT was positively related to CVD
incidence and a graded increase in CVD risk was observed
across GGT quartiles (Table 3). The association of GGT with
CVD was maintained in models incorporating CVD risk
factors as time-varying covariates (Table 3). A 1-SD incre-
ment in log-CRP was associated with a 1.20-fold (95%CI;
1.08 to 1.33, P⬍0.001) risk of incident CVD. After addition-
ally adjusting for serum creatinine concentration and educa-
tion level, a 1-SD increment in GGT was still associated with
a 15% increase in CVD (HR 1.15, 95%CI; 1.05 to 1.27,
P⫽0.004). Those in the highest GGT quartile had a 1.66-fold Figure 1. Age/sex-adjusted cumulative incidence of CVD by
GGT quartile. Numbers at risk are not the same in each quartile
risk (95%CI; 1.22 to 2.26, P⫽0.001), and a significant trend because cut points were determined on all participants with
was present across quartiles (P⬍0.001). available GGT data (before exclusions).
 Lee et al Gamma Glutamyl Transferase and CVD Risk and Mortality 131

factors, notably increased age, male sex, dyslipidemia, BMI,

glycemia, BP, and smoking. Second, higher serum GGT was
associated prospectively with increased incidence of the meta-
bolic syndrome, above and beyond conventional risk factors
including CRP. Third, serum GGT was positively associated
with incident CVD and death, after accounting for CRP and
hepatic enzymes. Because GGT was associated with the meta-
bolic syndrome prospectively, we adjusted for established CVD
risk factors as time-varying covariates, and the association of
GGT with CVD and mortality remained, suggesting that GGT
risk occurs by mechanisms other than promotion/development
of known risk factors. Overall, our data suggest that serum GGT
predicts development of the CVD risk factor cluster that consti-
tutes the metabolic syndrome, CVD events, and mortality.

Figure 2. Age/sex-adjusted cumulative incidence of mortality by

GGT quartile. Numbers at risk are not the same in each quartile
because cut points were determined on all participants with
available GGT data (before exclusions).
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Comparison With Prior Research
Prior studies suggested that higher GGT levels predicted
all-cause mortality in patients with myocardial infarction or

coronary artery disease,20,21 and in middle-aged individuals

including clinical covariates and log-GGT had a c-statistic of
0.799 (95%CI; 0.778 to 0.821), and addition of log-CRP
increased it minimally to 0.802 (95%CI; 0.780 to 0.823).
There was no significant interaction between GGT and CRP
for CVD or mortality prediction.
Discussion
Principal Findings
The principal findings of our investigations are three-fold. First,
serum GGT levels were related cross-sectionally to CVD risk
free of preexisting coronary disease.16,24 Prior studies were
limited by use of death certificate diagnoses of coronary heart
disease, and none addressed whether GGT predicted vascular
risk via promotion of established risk factors.16 Our observations
relating GGT to fatal and nonfatal incident CVD events in a
community-based sample complement prior studies reporting
that higher GGT is associated with cardiovascular death.33 We
expand on prior work by demonstrating that GGT is associated
with incident CVD even after accounting for baseline CRP, and
risk factors modeled as time-varying covariates.

TABLE 3. CVD Event Rates and Hazards Ratios According to GGT Levels
Log-GGT, 1-SD Quartile Quartile Quartile Quartile Quartile
Increment 1 2 3 4 Trend
% With Incident CVD
Events NA 10.5% 12.1% 16.7% 23.8% NA
Age/sex-adjusted rates/1000 NA 6.8 8.6 10.6 14.6 NA
person-years
Hazard Ratios (95% CI)
Models Adjusting for Conventional Risk Factors at Baseline§
Age/sex-adjusted 1.28* Referent 1.22 1.53‡ 2.11* 1.29*
(1.18–1.38) (0.92–1.62) (1.16–2.01) (1.63–2.74) (1.19–1.40)
Multivariable-adjusted 1.14‡ Referent 1.16 1.30 1.61* 1.17*
(1.04–1.24) (0.87–1.54) (0.98–1.72) (1.22–2.11) (1.08–1.28)
Models Adjusting for Conventional Risk Factors and CRP at Baseline§
Age/sex- and CRP-adjusted 1.20* Referent 1.28 1.53‡ 1.88* 1.23*
(1.10–1.31) (0.96–1.72) (1.15–2.04) (1. 43–2.48) (1.13–1.33)
Adjusted for multiple variables⫹CRP 1.11† Referent 1.23 1.35† 1.61‡ 1.16‡
(1.02–1.22) (0. 92–1.65) (1.01–1.81) (1.20–2.14) (1.06–1.27)
Models Adjusting for Conventional Risk Factors as Time-Varying Covariates and CRP at Baseline§
Multivariable-adjusted 1.16* Referent 1.19 1.38† 1.69* 1.19*
(1.07–1.26) (0.89–1.58) (1.05–1.82) (1.29–2.21) (1.10–1.29)
Adjusted for multiple variables⫹CRP 1.13‡ Referent 1.26 1.40† 1.67* 1.18*
(1.03–1.24) (0.94–1.68) (1.05–1.88) (1.25–2.22) (1.08–1.28)
Value of 1-SD log-GGT⫽0.6; NA⫽ not applicable; †P⬍0.05, ‡Pⱕ0.01, *Pⱕ0.001
§
Adjusted for age, sex, BMI, diabetes, systolic BP, total/HDL cholesterol ratio, current smoking, and alcohol consumption
 132 Arterioscler Thromb Vasc Biol. January 2007

TABLE 4. Mortality Rates and Hazards Ratios According to GGT Levels

Log-GGT, Quartile Quartile Quartile Quartile Quartile
1-SD Increment 1 2 3 4 Trend
% Mortality
Events NA 6.3% 7.4% 12.2% 16.1% NA
Age/sex-adjusted rates/1000 person-years NA 3.9 4.6 6.1 8.1 NA
Hazard Ratios (95% CI)
Models Adjusting for Conventional Risk Factors at Baseline§
Age/sex-adjusted 1.32* Referent 1.25 1.70‡ 2.21* 1.31*
(1.20–1.46) (0.87–1.79) (1.21–2.39) (1.60–3.05) (1.19–1.45)
Multivariable-adjusted 1.25* Referent 1.21 1.62‡ 1.94* 1.26*
(1.13–1.38) (0.84–1.74) (1.14–2.29) (1.38–2.73) (1.13–1.39)
Models Adjusting for Conventional Risk Factors and CRP at Baseline§
Age/sex- and CRP-adjusted 1.27* Referent 1.20 1.65‡ 1.94* 1.26*
(1.15–1.40) (0.83–1.74) (1.17–2.34) (1.39–2.72) (1.14–1.39)
Adjusted for multiple variables⫹CRP 1.23* Referent 1.17 1.61‡ 1.83* 1.23*
(1.10–1.37) (0.81–1.71) (1.13–2.29) (1.29–2.60) (1.11–1.37)
Models Adjusting for Conventional Risk Factors as Time-Varying Covariates and CRP at Baseline§
Downloaded from http://atvb.ahajournals.org/ by guest on June 12, 2018

Multivariable-adjusted 1.30* Referent 1.25 1.73‡ 2.16* 1.30*

(1.17–1.44) (0.87–1.79) (1.23–2.44) (1.54–3.02) (1.18–1.44)
Adjusted for multiple variables⫹CRP 1.26* Referent 1.21 1.67‡ 1.95* 1.26*
(1.13–1.40) (0.83–1.75) (1.18–2.37) (1.38–2.76) (1.13–1.40)
Value of 1-SD log-GGT⫽0.6; NA⫽ not applicable; †P⬍0.05, ‡Pⱕ0.01, *Pⱕ0.001
§
Adjusted for age, sex, BMI, diabetes, systolic BP, total/HDL cholesterol ratio, current smoking, and alcohol consumption

Although GGT was weakly correlated with CRP in our
sample and in prior studies,34 CRP did not abrogate the predic-
tive value of GGT for clinical events. First, adjustment for CRP
did not attenuate the association of GGT with CVD or mortality.
Second, there was minimal additional effect on model discrim-
ination when CRP was added to a model comprised of clinical
covariates and GGT. Finally, there was no statistical interaction
between GGT and CRP. Our findings suggest that GGT, a
routinely-available metabolic marker and indicator of oxidative
stress, is a significant predictor of CVD and mortality events
independent of CRP. Our findings suggest that GGT will be an
important component of future biomarker and multimarker
approaches to cardiovascular risk evaluation.
Potential Mechanisms of GGT Effect
Mechanisms that explain the contribution of GGT to CVD and
mortality have not been fully elucidated. GGT is associated with
hepatic steatosis35 and insulin resistance,22,23 and is a predictor of
incident hypertension36 and diabetes.13,37 Although we observed
that the relations of GGT to cardiovascular events and death
remained robust after accounting for fasting glucose and com-
ponents of the metabolic syndrome, it is conceivable that such
adjustment incompletely accounts for hepatic insulin resistance
and/or steatosis.38 The activity of ectoenzymatic GGT may also
modulate the redox status of protein thiols at the cell surface,
leading to production of reactive oxygen species and membrane-
permeable hydrogen peroxide.39 As noted previously, GGT
contributes to oxidative stress pathways in several organ sys-
tems, localizes to atheromatous plaques containing oxidized
LDL, and is proinflammatory, further implicating this protein in
atherogenesis.34,40,41
Strengths and Limitations
The strengths of our investigation are its prospective design,
consistent definition and validation of CVD events, complete
longitudinal ascertainment of deaths, accounting for risk factors
as time-varying covariates, and adjustment for CRP. The bio-
logical plausibility that GGT mediates vascular risk is reflected
by the strength of the associations, temporal relations between
baseline GGT and future vascular risk, and consistency of the
results across several analyses. Several limitations of our ap-
proach merit comment. Establishing that GGT is a “risk factor”
for CVD would require additional mechanistic studies that
further assess systemic oxidative stress, and evaluate hepatic
steatosis and insulin resistance. We did not obtain repeated GGT
or CRP measurements but used baseline values, which is a
potential limitation because changes could occur over time.23
Also, we did not extend this study to other emerging biomarkers
of vascular risk. Nonetheless, GGT assays are widely available
analytes which are routinely measurable in clinical laboratories.
Lastly, the overwhelming majority of our sample was white,
limiting the generalizability to other ethnicities.
Conclusions
In our community-based sample, higher GGT levels predicted
CVD, mortality, and development of the metabolic syndrome.
The association of GGT with adverse cardiovascular outcomes
and death was robust after adjustment for traditional cardiac risk
factors and CRP. Our study suggests that further investigation of
GGT will provide insights into the pathogenesis of CVD and
better define the clinical utility of this marker.
Sources of Funding
This work was supported by a Canadian Institutes of Health
Research clinician-scientist award (to D.S.L.), National Institute of
 Lee et al Gamma Glutamyl Transferase and CVD Risk and Mortality
Health/National Heart, Lung, and Blood Institute, contract N01-HC-
25195, and research grants R01HL073272 (to P.W.W.),
K23HL074077 (to T.J.W.), R01HL076784 (to E.J.B.),
N01HV28178 (to R.S.V.), R01HL71039 (to R.S.V.), R01HL67288
(to R.S.V.), and 2K24HL04334 (to R.S.V.).
Disclosures
None.
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Mortality Risk: The Framingham Heart Study

Douglas S. Lee, Jane C. Evans, Sander J. Robins, Peter W. Wilson, Irene Albano, Caroline S.
Fox, Thomas J. Wang, Emelia J. Benjamin, Ralph B. D'Agostino and Ramachandran S. Vasan

Arterioscler Thromb Vasc Biol. 2007;27:127-133; originally published online November 9,

2006;
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Online Table I. Multiple stepwise regression of GGT on clinical covariates

Variable β Estimate ΔR2 p-value

Triglyceride levels* 0.2318 0.1555 <0.001
Male 0.3019 0.0847 <0.001
Alcohol consumption† 0.1061 0.0401 <0.001
Diastolic blood pressure 0.0057 0.0195 <0.001
BMI 0.0150 0.0082 <0.001
Hypertension treatment 0.1658 0.0060 <0.001
Age 0.0027 0.0036 0.009
Current smoking 0.0354 0.0021 <0.001
LDL cholesterol 0.0010 0.0018 <0.001
Fasting glucose 0.0015 0.0016 0.004

*
Log-transformed triglyceride levels
†
Log-transformed weekly alcohol consumption